A critical feature of the immune system is its ability to respond specifically to antigens associated with invading pathogens while remaining tolerant of self antigens. Loss of self-tolerance can lead to debilitating and life-threatening autoimmunities. Self-tolerance is accomplished by a variety of mechanisms involving elimination of silencing of lymphoid cells bearing auto-reactive antigen receptors. Molecular mechanisms underlying these processes are poorly defined. We have developed a novel immunoglobulin transgenic mouse (mu/delta Ars/A1) in which B lymphocytes bear an antigen receptor that exhibits low affinity for an auto-antigen and high affinity the hapten p- azophenylarsonate (Ars). B cells develop in this mouse but are functionally silent, i.e. anergic. However, tolerance can be broken in these mice by repeated Ars-KLH immunization. Antigen receptors on these anergic B cells are competent to bind Ars but incompetent to transduce signals. Surprisingly, this receptor desensitization is rapidly relieved by incubation of cells with Ars hapten. These findings indicate that unresponsiveness is maintained by a constant low level signals transduced by auto-antigen bound receptors. Proposed studies will utilize biochemical, cell biological and genetic approaches to dissect molecular mechanisms underlying the disruption of receptor signaling in this model. They will also address the competence of anergic B cells to interact productively with Th lymphocytes. Finally, they will address the mechanism by which infrequent clones escape tolerance to produce auto- antibodies. The proposed studies will provide new insight regarding the molecular mechanisms underlying B cell anergy and loss of self-tolerance leading to auto-immunity.